Abstract. Pregnancy outwardly stimulates an assortment of changes in mothers that work together for creating the anatomical space that accommodates growth, nutrient exchange and elimination of waste products for the developing fetus. However, considering intimate physical approximation of maternal with fetal tissues which are genetically discordant, immunological changes that prevent mother?s immune cells from attacking and rejecting foreign fetal tissues are equally important. Unfortunately, how these immunological shifts work and what stimulates them during pregnancy remain poorly undefined. With these fundamental gaps in knowledge pertaining to how reproduction works unresolved, it should be no surprise that pregnancy complications remain the leading cause of infant and childhood mortality. We propose a more comprehensive understanding of how pregnancy works, integrating immunological with other physiological changes, is urgently needed for filling these knowledge gaps and uncovering new, more effective strategies for mitigating pregnancy complications. Our central hypothesis is that progesterone, the female reproductive hormone essential for maintaining uterine quiescence (averting premature uterine emptying), also promotes maternal immunological adaptations required for sustaining healthy term pregnancy. This hypothesis is based on increasingly recognized immune- modulatory properties for this highly conserved reproductive hormone. Our preliminary studies show progesterone drives differentiation of CD4+ T cells into an immune suppressive regulatory phenotype. The proportion of maternal regulatory T cells increase in the circulation and at the maternal-fetal interface during healthy pregnancy, whereas a variety of complications linked with disrupted fetal tolerance (e.g. prematurity, preeclampsia, miscarriage) are associated with blunted expansion of these cells. Maternal regulatory T cells expansion is similarly overturned with abortion induced by the nuclear progesterone receptor antagonist, RU- 486. We also find a variety of maternal immune cells in systemic lymphoid tissues and at the maternal-fetal interface express the canonical nuclear progesterone receptor. This includes maternal regulatory T cells, and in particular those recognizing genetically foreign fetal-expressed antigens. Reciprocally, selective loss of progesterone receptor in maternal regulatory T cells blunts their expansion during pregnancy causing fetal wastage. Based on these exciting proof-of-concept preliminary findings showing the protective benefits of progesterone stimulation of maternal immune cells, the following aims will more comprehensively investigate progesterone induced systemic and local immunological changes required for maintaining pregnancy. Aim 1 will investigate the tempo of progesterone responsiveness amongst maternal immune cells during pregnancy. Aim 2 will define which maternal immune cell subsets require progesterone responsiveness for maintaining pregnancy. Aim 3 will evaluate how maternal immune cell progesterone responsiveness impacts the efficacy of 17 a-hydroxyprogesterone caproate in protecting against recurrent preterm birth.